Sunday, October 25, 2015

University of Wisconsin 3rd Annual Update

I just finished the 3rd Annual Update and Advances in Psychiatry at the University of Wisconsin in Madison Wisconsin. It is familiar turf to me because that is where I finished psychiatric residency training. I was impressed with the first two updates and have covered my experience at the 1st Annual and 2nd Annual Updates on this blog in the past. During the introductory comments, the Department Chair Ned Kalin, MD paid tribute to John Greist, MD and James "Jeff" Jefferson, MD who ran the conference for 37 years before it was taken over by the Department of Psychiatry.

The absolute high point of day one was a discussion of schizophrenia by Daniel Weinberger, MD. I had seen him speak before. In talking with Dr. Kalin about the conference Dr. Weinberger gave a more research oriented talk the day before in the department that was focused on more science and neuroscience that I wish I had seen, but the lecture he gave to clinicians at this conference was outstanding. From the introduction Dr. Weinberger had apparently left the NIMH and is now working as Director and CEO and for the Lieber Institute for Brain Development. They have quite a unique website and faculty. The title of his discussion was Neurobiology of psychosis in the era of genetic medicine and he offered some unique perspectives that I doubt are available in many places. It was useful to see a focus on schizophrenia in a conference of this nature and a focus on how at least some of the cutting edge research is looking at therapeutic modalities that are unique rather than the usual isomeric approach to drug discovery. It was also refreshing to hear that there is optimism out there rather than the usual doom and gloom about the the "pipeline" from Big Pharma is running dry and there will be limited options for the future.

The Weinberger lecture had an interesting introduction that focused on brain imaging studies in psychiatric disorders. It was well done, well argued, and based on his American J Psychiatry article that was published earlier this year (2). He points out that while brain imaging has been the "centerpiece" of neuropsychiatric research that it is still fraught with technical difficulties. In many of the articles that seem to make the lay press there is almost nothing that is not associated with brain changes. He showed examples attempting to correlate viewing pornography with the frontostriatal network, increased gray matter volume secondary to lithium use, and other common artifacts and he concludes that most illness associated imaging findings are likely epiphenomenal. To anyone trained as a chemist in their undergrad major who has experience with nuclear magnetic resonance (NMR) scanning of organic molecules a lot of this comes as no surprise. To anyone used to reading decades of similar research (like quantitative EEG) and realizing that the pilot studies never panned out even after some were published in very prestigious journals this should also not come as a surprise. Weinberger offered the technical explanations for why these issues occur and also some studies that seemed to be sound.

The bulk of his lecture was dedicated to the genetics of schizophrenia. The opening slide not only contained a lot of information it was a tutorial in how to present information in PowerPoint format. It was titled "The emerging genetics of schizophrenia". In the upper left corner was a graphic from Gottesman's work with 11 bar graphs above the same axis showing risk for schizophrenia based on relationship to the index case. Right below that was a table of Exome Sequencing: Rare Variants showing rare structural variants in schizophrenia with the title of a report to the right. In the upper right hand corner was a Manhattan plot of 108 GWAS loci on all human chromosomes and the reference to the report in Nature. It was a beautiful slide in terms of presentation and information content.

He went on to discuss genome-wide association studies (GWAS) and what they imply for the genetics of schizophrenia. Inheritance of schizophrenia is widely considered to be polygenic and has been for some time. He framed this issue as there being no psychiatric disorder gene and I thought that was a useful reframing because it speaks to studies that are looking at a very few point mutations associated with schizophrenia, and it is easy to think that this gene is the cause of schizophrenia rather than conferring risk for the disorder. He demonstrated this with a risk profile score (RPR) for developing schizophrenia based on an additive count of all risk alleles. In the example given the risk profile for the highest risk score had an odds ration of 15-20 to 1 for developing schizophrenia. He went on to review the evidence for schizophrenia as a neurodevelopmental disorder. That included some epidemiological data such as artificially imposed famine in China and the Netherlands and the subsequent increase in the incidence of schizophrenia in the respective birth cohorts (1). He showed that de novo mutation in schizophrenia overlap with more traditional neurodevelopmental disorders like autism spectrum disorder and intellectual disability. He showed that genes from all three disorders are overexpressed during the fetal period and this is a pattern seen in neurodevelopmental disorders.

This was compelling stuff. I come to this conference very year to get rejuvenated and it worked again this year. The only regret I had was that time has just about run out for me. I am no longer a young science major with an interest in human behavior and how the brain works. I don't have time to go back and do a fellowship with Dr. Weinberger or a sleep fellowship or any number of other interesting things that I see at conferences. I can understand the concepts, teach them, and advise younger colleagues and residents on what is available and why this is a compelling field whenever I can. I can also continue to get the word out that psychiatry is alive and well, that the best critics of psychiatry are trained as psychiatrists, and what passes for psychiatric criticism on blogs and in the press lacks a critical element called scholarship. And as important - you don't have to be Kandel or Weinberger to be scholarly and apply what you know about the science to what you do every day as a psychiatrist. Equally important - knowing the theory and what can and cannot be applied yet - is an important aspect of being a physician.

It was a good weekend.

George Dawson, MD, DFAPA

References:

1: Schizophrenia and famine collection (original articles on the Dutch and Chinese famine are references number 39 and 59):